Acetyl CoA carboxylase (ACC) catalyzes the first committed step in fatty acid biosynthesis, and therefore is an essential enzyme in most organisms. This makes ACC an attractive agrochemical target and ACC is chemically validated as a fungicide, herbicide, and insecticide target as described in more detail in Elich et al., U.S. Patent Application Publication No. 2004/0086994. Additionally, ACC plays a crucial role in the metabolism of fatty acids in mammals and therefore has been used as a target for drug development against obesity, diabetes, cancer and other diseases (Abu-Elheiga, L. et al., Science 291, 2613-2616 (2001); Alberts, A. W., and Vagelos, P. R. Acyl-CoA Carboxylases. In The Enzymes, P. D. Boyer, ed. (New York, Academic Press), pp. 37-82 (1972); Cronan Jr., J. E., and Waldrop, G. L., Prog Lipid Res 41, 407-435 (2002); Harwood Jr., H. J. et al., J Biol Chem 278, 37099-37111 (2003); Wakil, S. J. et al., Ann Rev Biochem 52, 537-579 (1983); Zhang, H. et al., Structure 12, 1683-1691 (2004); Zhang, H. et al., Proc Natl Acad Sci USA 101, 5910-5915 (2004); Zhang, H. et al., Science 299, 2064-2067 (2003)). ACCs catalyze the carboxylation of acetyl-CoA to produce malonyl-CoA. Mammals have two isoforms of ACC, ACC1 and ACC2. ACC1 is present in the cytosol of liver and adipose tissues and controls the committed step in the biosynthesis of long-chain fatty acids. In comparison, ACC2 is associated with the outer membrane of mitochondria in the heart and muscle. Its malonyl-CoA product is a potent inhibitor of carnitine palmitoyltransferase I, which facilitates the transport of long-chain acyl-CoAs into the mitochondria for oxidation (McGarry, J. D. et al., Eur J Biochem 244, 1-14 (1997); Ramsay, R. R. et al., Biochim Biophys Acta 1546, 21-43 (2001)). The importance of ACCs for drug discovery is underscored by the observations that mice lacking ACC2 have elevated fatty acid oxidation, reduced body fat and body weight (Abu-Elheiga, L. et al., Proc Natl Acad Sci USA 100, 10207-10212 (2003); Lenhard, J. M. et al., Advanced Drug Delivery Reviews 54, 1199-1212 (2002)).
Additionally, it is well known that de novo lipogenesis is required for the growth of many tumor cells and that ACC is upregulated in many cancer cells (Milgraum et al., Clin Cancer Res 3:2115-20 (1997); Swinnen et al., Int J Cancer 88:176-9 (2000); Zhan et al., Clin Cancer Res 14:5735-5742 (2008)). The importance of ACC as an anti-cancer target is underscored by the observations that the ACC inhibitor soraphen induces growth arrest and selective cytotoxicity in cancer cells (Beckers et al., Cancer Res 67:8180-8187 (2007)), and that RNA interference-mediated down-regulation of ACC inhibited growth and induced apoptosis in breast cancer cells (Chajes et al., Cancer Res 66:5287-5294 (2006)) and in HCT-116, PC-3, and A2780 cancer cells (Zhan et al., Clin Cancer Res 14:5735-5742 (2008)).
Diseases including, but not limited to, Alzheimer's Disease, Parkinson Disease, Huntington's Disease, epilepsy and Mild Cognitive Impairment are associated with reduced neuronal metabolism. Inhibition of ACC leads to increases in fatty acid oxidation and corresponding increases in blood ketone body levels that can provide an alternative energy source for neuronal cells with compromised metabolism. For example, in the brain, blood glucose provides the typical source of energy; however, under some circumstances ketone bodies can provide an alternative energy source. Alzheimer's Disease appears to result from a decreased metabolic rate in the brain due to a reduction in glucose utilization. Induction of ketosis by oral administration of medium chain triglycerides improves the cognitive performance of probable mild to moderate Alzheimer's disease subjects (U.S. Pat. No. 6,835,750) and elevation of serum ketone body levels in Alzheimer's Disease patients raises cognitive scores (Reger et al. Neurobiol. Aging 3:311-314 (2004)).